Changes in protein expression with age fundamentally alter the brain micro-environment. How changes in expression of specific proteins impact brain aging and development of disease remains poorly understood. Klotho, originally described as longevity protein, is age-downregulated in brain and promotes cognitive impairment or enhancement dependent on its level of protein expression. Our preliminary data show a role for klotho in both postnatal neurogenesis and synaptic plasticity of the hippocampus. Hippocampal function is critical in cognitive function and is particularly sensitive to the effects of advanced age. Klotho mediated effects on hippocampal function could underlie cognitive effects measured in knockout and overexpressing animals. The long-term goal of the proposed research is to understand the functional consequences on cognition caused by age-downregulation of klotho and thus how klotho affects hippocampal function over lifespan. Using mouse and viral vector models of klotho protein expression level differences, the central hypothesis that klotho expression is required for sustained hippocampal function with age will be interrogated. The hypothesis is based on preliminary data revealing differences in the neural stem cell development and synaptic plasticity concomitant with increased or decreased expression of klotho protein. To investigate the hypothesis three specific aims will be conducted: 1) Test the hypothesis that brain-derived klotho expression regulates hippocampal function by inhibition of neurotrophic signaling; 2) Determine whether long-term loss of brain- derived klotho causes hippocampal degeneration; 3) Test whether enhanced klotho expression is sufficient to prevent cognitive aging. In specific aim 1, we will utilize our novel mouse models to determine whether klotho in the brain mediates cognitive outcomes. Aim 2 will determine whether the rapid onset of cognitive impairment and markers of stress in the global klotho knockout are the precursors to neurodegeneration. Aim 3 will test whether klotho can be elevated in mid-life to support healthy brain aging. The work is significant in identifying a role for klotho in normal bran function and provides new information as to whether klotho's effects on cognition are mediated by its role in neurogenesis or synaptic plasticity. The application is innovative in its use of anial models to allow targeted manipulation of klotho expression level. By understanding how klotho functions in the brain, we will obtain greater insight into mechanisms underlying both normal brain aging and pathological disease development.